The compound 1-(N2-[(S)-1-carboxy-3-phenylpropyl]-L-lysyl)-L-proline, having the generic name lisinopril, as well as therapeutically acceptable salts thereof, are described in U.S. Pat. Ser. No. 4,374,829 (Merck and Co. Inc.), incorporated herein by reference. In said patent the compound is described in Example 119, and is referred to as N-xcex1-[1(S)-1-carboxy-3-phenylpropyl]-L-lysyl]-L-proline. The divisional application to this patent, which has resulted in U.S. Pat. No. 4,472,380, incorporated herein by reference, claims pharmaceutical compositions that include lisinopril pharmaceutical compositions. Lisinopril is a drug on which extensive clinical experience has been obtained. It is currently sold under the trademark ZESTRIL(copyright) or PRINIVIL(copyright).
Lisinopril is a peptidyl dipeptidase inhibitor useful in treating cardiovascular diseases and disorders, such as hypertension and congestive heart failure (CHF) in mammals and especially in man. It inhibits the angiotensin converting enzyme (ACE) that catalyses the conversion of angiotensin I to the vasoconstrictor peptide, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE results in decreased concentrations of angiotensin II which results in decreased vasopressor activity and reduced aldosterone secretion.
ACE is known to be present in the endothelium and increased ACE activity in diabetic patients which results in the formation of angiotensin II and destruction of bradykinin, potentiates the damage to the endothelium caused by hyperglycaemia. ACE inhibitors, including lisinopril, inhibit the formation of angiotensin II and breakdown of bradykinin and hence ameliorate endothelial dysfunction.
In terms of the pharmacokinetic properties of lisinopril, following oral administration, peak serum concentrations occur within about 7 hours, although there is a trend to a small delay in time taken to reach peak serum concentrations in acute myocardial infarction patients. On multiple dosing lisinopril has an effective half-life of accumulation of about 12.6 hours. Declining serum concentrations exhibit a prolonged terminal phase, which does not contribute to drug accumulation. This terminal phase probably represents saturable binding to ACE and is not proportional to dose. Based on urinary recovery, the mean extent of absorption of lisinopril is approximately 25%, with interpatient variability (6-60%) at all doses tested (5-80 mg). Lisinopril does not undergo metabolism and absorbed drug is excreted unchanged entirely in the urine.
The monohydrate form of lisinopril of the present invention, (herein xe2x80x9cmonohydrate lisinopril form 2xe2x80x9d) is different from the monohydrate form of lisinopril (xe2x80x9cmonohydrate lisinopril form 1xe2x80x9d) previously reported by Ip et al., (Lisinopril, in Analytical Profiles of Drug Substances and Excipients (Ed., Brittain, H. G.), Academic Press, Volume 21, pp 233-276, 1992). The only characterising data of the monohydrate in this publication is an X-ray powder diffraction (XRPD) pattern shown as a plot of intensity of diffracted x-rays vs xc2x02xcex8 (FIG. 12, p257). No other analytical data or description of the monohydrate is given, nor is its preparation described. Despite this lack of teaching of how to make the monohydrate of Ip et al., the inventors have managed not only to prepare the new monohydrate (denoted monohydrate lisinopril form 2) of the present invention, but also what is believed to be the monohydrate disclosed by Ip et al., (denoted monohydrate lisinopril form 1).
Monohydrate lisinopril form 2 is also different from the xe2x80x9cmonohydratexe2x80x9d that is disclosed in Wang, S-L. et al., 2000, Chem. Pharm. Bull. 48, 1890-93. Wang et al. describes the generation of a lisinopril xe2x80x9cmonohydratexe2x80x9d by heating lisinopril dihydrate until weight loss corresponding to one mole of H2O per mole of lisinopril was observed. The present inventors have performed the identical experiment as Wang et al. and have found that the resulting xe2x80x9cmonohydratexe2x80x9d is strongly hygroscopic, i.e., the evolved water is quickly reabsorbed from the atmospheric water when the crystals are returned to room temperature. By contrast, both form 1 and form 2 monohydrates of the invention are stable at a standard room temperature and humidity.
The monohydrate lisinopril form 2 of the present invention is substantially more soluble than the dihydrate of lisinopril (Zestril), and in view of this increased solubility, it may prove more suitable for the preparation of a xe2x80x98fast meltxe2x80x99 tablet formulation than conventional lisinopril dihydrate.
The present invention relates to a novel monohydrate form of 1-(N2-[(S)-1-carboxy-3-phenylpropyl]-L-lysyl)-L-proline. 1-(N2-[(S)-1-carboxy-3-phenylpropyl]-L-lysyl)-L-proline is known under the generic name lisinopril and its novel monohydrate form is hereinafter referred to as monohydrate lisinopril form 2. The present invention further relates to the use of monohydrate lisinopril form 2 in medical treatments, pharmaceutical compositions comprising monohydrate lisinopril form 2, in particular xe2x80x98fast meltxe2x80x99 formulations, and processes for the preparation of monohydrate lisinopril.
Monohydrate lisinopril form 2 can be characterized by several different criteria. By one criterion, monohydrate lisinopril form 2 is the crystal form of lisinopril that results from the precipitation of lisinopril by the process of dissolving any form of lisinopril in water, forming a crystalline precipitate by the addition of excess isobutanol and drying the precipitate that has been formed at a temperature of not more than 80xc2x0 C. By another criterion, monohydrate lisinopril form 2 is the crystalline form of lisinopril that is characterized as having an XRPD pattern that has strong or very strong peaks at 2-d spacings of 12.0 and 11.5xc3x85. Additional criterion for the identification of monohydrate lisinopril from 2 are set forth in the detailed description of the invention. Such criteria include: further characterisations of the XRPD pattern; temperature of the onset of melting and temperature of the peak of the endotherm; a characteristic infrared (IR) absorption spectrum; and a characteristic Raman spectrum.